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EFE 2012

Maria Rosaria Ambrosio

Dipartimento di Scienze Mediche

Sezione di Endocrinologia

Direttore Prof. Ettore degli Uberti

Universit degli Studi di Ferrara

INQUADRAMENTO

DIAGNOSTICO DEI

TUMORI NEUROENDOCRINI

DEL PANCREAS

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

Prevalenza 4-12 casi/milione di abitanti

Tumori neuroendocrini pancreatici

Funzionanti

Non funzionanti (~ 40%) Insulinoma (~26%)

Gastrinoma (~18%)

VIPoma (~5%)

Glucagonoma (~6%)

Somatostatinoma (~3%)

Sporadici

Associati a Neoplasie Endocrine di Tipo 1 (40-100% dei pz con MEN1) spesso multiplo e non funzionante causa pi frequente di morte nei pz MEN1 a Sdr. di von Hippel-Lindau (12-20% dei pz con VHL)

Tumori secernenti ormoni ectopici (~2%)

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

Et media 58.614.7 anni F= 51.2 %, M= 48.8%

Funzionanti: 73 (24.6%)

NON Funzionanti: 232 (75.4%)

Insulinomi:53

Gastrinomi:15

Altre secrezioni: 5

115 casi (38.7%), diagnosi incidentale

Zerbi A et al. Am J Gastroenterol. 2010;105:1421

Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases

Lesperienza italiana

Sporadici: 35 (87.5%) Associati a MEN1: 5 (12.5%)

Non funzionanti: 22 (55%) Funzionanti: 18 (45%)

Insulinomi:10 (55.5%)

Gastrinomi:3 (16.6%)

Vipomi:2 (11.1%)

Glucagonomi: 1 (5.5%)

Tumori secernenti ormoni ectopici (calcitonina):2 (11.1%)

casi: 40 M= 16 (40%) F= 24 (60%) Et media alla diagnosi: 62 anni (range: 16-92 anni)

Carcinomi neuroendocrini: 20 (50%) Tumori neuroendocrini: 15 (37.5%) Ad istologia non specificata: 5 (12.5%)

Con metastasi: 12 (66.6%)

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

Tumori neuroendocrini pancreatici

Lesperienza di Ferrara

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

WORK-UP DIAGNOSTICO

Esame istologico determinante per la strategia terapeutica

Imaging Valutazione del tumore primario e

della estensione della malattia

Markers immunoistochimici

Valutazione biochimica Markers tumorali specifici e aspecifici

Kjell berg Clinics 2012;67(S1):109

EFE 2012

LA DIAGNOSI SI BASA su

STORIA FAMILIARE

SEGNI E SINTOMI CLINICI

INDAGINI DIAGNOSTICHE per IMMAGINI:

Tomografia Computerizzata

Risonanza Magnetica

Ecografia

Endoscopia

Ecoendoscopia (EUS)

Scintigrafia per SSR

Angiografia

ISTOLOGIA

INDAGINI DI LABORATORIO

- PARAMETRI BIOCHIMICI -

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

incidence 13/million population/year

< 10% are malignant ~ 10% are multiple

~ 5% are associated with the MEN1 syndrome

Tumor size 2 cm, Ki67 > 2% and various molecular features (chromosomal instability; chromosomal loss of 3p or 6q; chromosomal gain on 7q, 12q or 14q) all are predictors of metastatic disease, which is associated with decreased survival

INSULINOMA

Jensen RT et al Neuroendocrinology 2012;95:98

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

ages 40-45 years females 60%

Clinical Presentation

The symptoms are due to the effects of hypoglycemia

Jensen RT et al Neuroendocrinology 2012;95:98

INSULINOMA

on the CNS confusion, visual disturbances, headaches, behavioral changes, coma

on the adrenergic system sweating, tremor, palpitations, irritability

A recent increase in body weight is present in the majority of patients

The mean duration of symptoms at diagnosis is 3 years

documented blood glucose levels 2.2 mmol/L (40 mg/dL)

concomitant serum insulin levels 6 mU/L ( 36 pmol/L; 3 mU/L by ICMA)

plasma/serum C-peptide levels 200 pmol/L

serum proinsulin levels 5 pmol/L

serum b-hydroxybutyrate levels 2.7 mmol/L

absence of sulfonylurea (metabolites) in the plasma and/or urine

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

INSULINOMA

DIAGNOSIS

de Herder WW. Best Practice & Research Clinical Endocrinology & Metabolism 2007; 21,:33.

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

INSULINOMA

de Herder WW. Best Practice & Research Clinical Endocrinology & Metabolism 2007; 21,:33.

72-hour fast gold standard test

When the patient develops symptoms and the blood glucose levels are 2.2 mmol/L (40 mg/dL), blood is also drawn for

C-peptide, proinsulin and insulin determinations

DIAGNOSIS

Failure of appropriate insulin suppression in the presence of hypoglycaemia substantiates an

autonomously secreting insulinoma

Some of these tumours produce more proinsulin than insulin

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

INSULINOMA

DIAGNOSIS

PROINSULINOMA

The diagnosis may be erroneously missed using

only insulin ELISA, IRMA or ICMA

Insulin RIAs

generally have cross-reactivity with proinsulin

therefore do not produce these diagnostic problems

de Herder WW. Best Practice & Research Clinical Endocrinology & Metabolism 2007; 21,:33.

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

incidence 0.52/million population/year

According to WHO 2010 gastrinomas are NET G1-G2, usually >1 cm, showing local invasion and/or proximal lymph node metastases

Liver metastases occur much more frequently with pancreatic gastrinomas (2235%) than duodenal gastrinomas (010%)

Pancreatic gastrinomas are generally large in size (mean 3.8 cm, 6% < 1 cm), duodenal gastrinomas are usually small (mean 0.93 cm, 77% < 1 cm)

While the pancreatic gastrinomas may occur in any portion of the pancreas, duodenal gastrinomas are predominantly found in the first part of the duodenum including the bulb

At surgery, 7085% of gastrinomas are found in the right upper quadrant (duodenal and pancreatic head area), the so-called gastrinoma triangle

Immunohistochemically, almost all gastrinomas stain for gastrin

GASTRINOMA

Jensen RT et al Neuroendocrinology 2012;95:98

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

2030% of patients with ZES

Duodenal tumors are usually (70100%) responsible for the ZES

Duodenal tumors are almost always multiple

Histologically, most gastrinomas are well differentiated and show a trabecular and pseudoglandular pattern Their proliferative activity (i.e. the Ki67 index) varies between 2 and 10%, but is mostly close to 2%

GASTRINOMA

MEN 1

Jensen RT et al Neuroendocrinology 2012;95:98

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

GASTRINOMA

All of the symptoms

except those late in the disease course

are due to gastric acid hypersecretion

Jensen RT et al Neuroendocrinology 2012;95:98

Clinical Presentation

ages 4855 years males 5456%

sporadic gastrinomas

The mean delay in diagnosis from the onset of symptoms is 5.2 years

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

GASTRINOMA

Several other tests have also been described that may still have an adjunctive role, particularly when secretin is unavailable

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

GASTRINOMA DIAGNOSIS

Fasting serum gastrin concentration

Secretin stimulation test

Gastric acid secretion studies

Jensen RT et al Neuroendocrinology 2012;95:98

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

physiologic level < 100 pg/mL is elevated in > 98% of all ZES patients alone does not establish the diagnosis because of the many other causes of hypergastrinemia

Fasting serum gastrin (FSG)

Jensen RT et al Neuroendocrinology 2012;95:98

GASTRINOMA DIAGNOSIS

renal insufficiency

massive small bowel resection

G-cell hyperplasia

gastric outlet obstruction

retained gastric antrum

with normal or slightly increased gastric acid secretion

chronic atrophic fundus gastritis often associated with pernicious anemia

Cause of hypergastrinemia

with hypochlorhydria/achlorhydria

EFE 2012

Inquadramento diagnostico dei tumori neuroendocrini del pancreas

Fasting serum gastrin (FSG)

FSG level 1000 pg/mL gastric pH 2

in 2/3 of patients with the ZES

FSG level >150 and

Recommended

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